The objective of this proposal is to develop a broadly available, reliable diagnostic test for early Parkinson's disease (PD) using functional magnetic resonance imaging (fMRI). PD is one of the most common neurodegenerative disorders, affecting over 1 million people in the United States. It causes significant human suffering and has annual cost of approximately 24 billion dollars in health care resources and lost wages. Clinical and research efforts in PD are hampered by the lack of a widely available objective test for this disease. Although PET and SPECT imaging provide the best objective testing currently available, they are limited by lack of widespread availability, high cost, relatively poor resolution and the use of ionizing radiation. Recent advances in fMRI allow for imaging of neuronal activation along the entire brain motor pathway including the brainstem and basal ganglia during the performance of a complex motor task. These techniques have been successfully applied to both normal subjects and PD patients. Normal subjects demonstrate symmetric activation along the entire motor pathway whereas PD patients demonstrate asymmetric activation with decreased neuronal activation along the motor pathway contralateral to their symptomatically more affected side. The degree of asymmetry has been quantitatively studied using a newly developed cluster analysis technique and demonstrates significant differences between normal individuals and early PD patients. The present application seeks to expand and refine these techniques to produce a clinically applicable diagnostic fMRI test for PD. The application is divided into two phases: a development phase (year 1 of the proposal) and trial phase (years 2 and 3 of the proposal). The development phase will study both patients with early PD and normal subjects to address two specific aims: 1) modification of the existing fMRI protocol in order to make it shorter and easier to perform while maintaining the robust activation achieved presently and 2) rigorous quantification of motor task performance to establish minimum performance criteria. The overall goal of the development phase is to produce a well-characterized fMRI protocol that can be applied in the clinical setting to obtain consistent results. The trial phase will test the newly developed fMRI protocol on a group of patients with early PD and normal subjects. The specific aim of the trial phase will be to test the hypothesis that early PD patients can be distinguished from normal subjects by quantitative measurement of asymmetric fMRI motor pathway activation. A widely available, reliable diagnostic fMRI test for early PD would be useful in both the clinical and research settings. Potential future applications include the detection of preclinical disease, monitoring disease progression and differentiation of PD from parkinsonian syndromes. A single test that could address all of these potential applications would represent an effective diagnostic gold standard for PD. The present proposal represents a first step toward the development of such a gold standard.